News beyond our pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2023)

Currently available options to prevent hereditary angioedema attacks are limited. Because of this, Craig et al (Lancet 2023 Feb 28; https://doi.org/10.1016/S0140-6736(23)00350-1) performed a randomized, placebo-controlled phase 3 trial assessing the efficacy of garadacimab, an inhibitory mAb directed against activated factor XII, for in prophylaxis against hereditary angioedema attacks. Subjects were treated for 6 months with once-monthly subcutaneous injections of garadacimab or placebo. Garadacimab significantly reduced the rate of hereditary angioedema attacks, days with symptoms, and need for on-demand (rescue therapy) and improved quality of life. Garadacimab was generally well-tolerated and did not increase the risk of bleeding or thromboembolism. These findings support the use of garadacimab for prophylaxis in hereditary angioedema. We asked corresponding author Timothy J. Craig, DO, of the Department of Medicine, Section of Pulmonary, Allergy and Critical Care at Penn State University, Hershey, Pennsylvania, to comment on the study. He writes, “This study confirmed that garadacimab given once a month by the subcutaneous route is very effective with infrequent dosing and should provide an increase in quality of life secondary to the reduction of attacks and drug burden compared to presently approved medications for hereditary angioedema.” Signal transducer and activator of transcription 6 (STAT6) is a key transcription factor that orchestrates allergic inflammation. Sharma et al (J Exp Med 2023 May 1; https://doi.org/10.1084/jem.20221755) identified 16 patients from 10 geographically disparate families with monoallelic rare gain-of-function mutations in STAT6. Striking allergic immune dysregulation was observed with multiple severe chronic allergic diseases, elevated serum IgE levels, and enhanced IgE-mediated food allergies and anaphylaxis. Notably, blocking the IL-4 signaling axis with the mAb dupilumab improved both clinical manifestations and biomarkers of TH2 inflammation. Collectively, these results identify gain-of-function STAT6 variants as a novel primary atopic disorder that may be therapeutically targetable with dupilumab. Image attribution Wikimedia by user Skoch3, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons. We asked first author Mehul Sharma, PhD, and corresponding author Stuart E. Turvey, MBBS, DPhil, FRCPC, both of The University of British Columbia, Vancouver, British Columbia, Canada, to comment on the study. They write, “Our findings will accelerate the diagnosis and treatment of individuals with severe allergic disease caused by gain-of-function STAT6 variants, while also identifying molecular mechanisms driving human allergic inflammation. We recommend genetic testing for patients who experience severe allergic disease beginning very early in life.”Mehul Sharma and Stuart E. TurveyView Large Image Figure ViewerDownload Hi-res image Download (PPT) Identification of specific trigger foods in patients with eosinophilic esophagitis (EoE) is impossible without dietary exclusion. Because of this, empiric elimination diets are utilized to induce remission, although they are often limited by patient nonadherence due to their restrictive nature. Kliewer et al (Lancet Gastroenterol Hepatol 2023 Feb 27; https://doi.org/10.1016/S2468-1253(23)00012-2) conducted a randomized, open-label multicenter trial comparing dietary elimination of 6 common food allergens (animal milk, wheat, egg, soy, fish, and nuts; termed the 6-food elimination diet [6FED]) versus milk alone (termed the 1-food elimination diet [1FED]). Notably, similar rates (35%-40%) of histologic and endoscopic remission were observed with both diets. Furthermore, approximately half of the subjects who failed 1FED achieved remission after transitioning to 6FED. In total, these results support using a minimally restrictive diet with single elimination of animal milk initially for treatment of EoE with step-up to 6FED if necessary. Image attribution Wikimedia by user Samir at the English-language Wikipedia, CC BY-SA 3.0 <http://creativecommons.org/licenses/by-sa/3.0/>, via Wikimedia Commons.Similar rates of histologic and endoscopic remission were observed Similar rates of histologic and endoscopic remission were observed We asked co-first author Kara Kliewer, RD, PhD, of the Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, to comment on the study. She writes, “Our work shows that starting with the elimination of animal milk only is an acceptable alternative to starting with the more difficult 6-food elimination diet for the treatment of eosinophilic esophagitis. In practical terms, these findings may result in patients seeing diet elimination therapy as a more desirable therapy that can more practically serve as an alternative to pharmacologic therapies.” Building upon prior observational studies that identified an association between prenatal and early-life use of acid suppressive therapy and allergic disease, Noh et al (JAMA Pediatr 2023;177:267-77; https://doi.org/10.1001/jamapediatrics.2022.5193) performed a nationwide population-based cohort study involving over 4 million South Korean mother-child pairs. After controlling for co-morbid conditions and within-familial factors, acid suppressive therapy use in infancy increased the risk of asthma later in life. Conversely, increased risk of allergic disease was not observed with prenatal exposure to acid suppressive medications. Notably, results were consistent between both histamine 2 receptor antagonists and proton pump inhibitors. Collectively, these findings suggest that infant, but not prenatal, exposure to acid suppressive therapy increases the risk of subsequent allergic disease. We asked corresponding author Ju-Young Shin, PhD, of the School of Pharmacy, Sungkyunkwan University, Suwon, South Korea to comment on the study. She writes, “I hope that our study will be used as an important evidence for pregnant women and their newborns to take medicine safely.” Silverberg et al (N Engl J Med 2023 Mar 15; https://doi.org/10.1056/NEJMoa2206714) performed 2 identically designed placebo-controlled phase 3 trials to assess the efficacy of lebrikizumab, an mAb that specifically inhibits IL-13 signaling without interfering with IL-4 signaling, in adult and adolescent patients with moderate-to-severe atopic dermatitis who were eligible for systemic therapy. After 16 weeks of induction therapy, lebrikizumab improved skin clearance and patient-reported symptoms, including itch and interference with sleep by itch, in both trials. Importantly, lebrikizumab showed a good safety profile and was well-tolerated. The results of this study demonstrate that short term use of lebrikizumab improves both signs and symptoms of atopic dermatitis, and further investigations into longer term efficacy and safety are ongoing. We asked corresponding author Jonathan I. Silverberg, MD, PHD, MPH, of the George Washington University School of Medicine and Health Sciences, Washington, DC, to comment on the study. He writes, “We showed that lebrikizumab was safe and highly effective for the treatment of moderate-severe AD. These studies will hopefully support the approval of lebrikizumab in the United States and around the world later this year.”News items were written by medical writer Jared Travers, MD, PhD. News items were written by medical writer Jared Travers, MD, PhD.